PHILADELPHIA ( TheStreet) --Three years after being rejected by U.S. Food and Drug Administration, Hemispherx Biopharma ( HEB) is back seeking regulatory approval for Ampligen, its controversial therapy for chronic fatigue syndrome. Everyone loves a comeback story with a happy ending, but Hemispherx's second attempt won't turn out any happier than the first. FDA is likely to reject Ampligen again because Hemispherx ignored the agency's demand to run a new clinical trial in chronic fatigue syndrome. Instead, Hemipsherx has spent the past three years doing essentially nothing but re-analyzing data from the old Ampligen phase III trial completed in 2004. FDA reviewed the original study already, deeming it "lacking credible evidence of efficacy of Ampligen." It would be highly unusual -- unprecedented, even -- for FDA to reverse itself and find a retrospective rehash of old Ampligen data more compelling this time around. FDA has been facing political pressure to speed new drugs to market, particularly for diseases like chronic fatigue syndrome with no current treatments. But this hardly means FDA is going to throw out its drug-review rulebook. FDA has scheduled an advisory panel for Dec. 20 to review Hemispherx's Ampligen resubmission. The agency is expected to issue a final approval decision on or before Feb. 2, 2013. Ampligen's long odds haven't deterred speculators from bidding up Hemispherx's stock price, just like they did in 2009. At Wednesday's close of 90 cents, Hemispherx shares are up more than 220% since July 11 when the company announced plans to resubmit Ampligen for FDA approval. For those that don't remember, the phase III study enrolled 234 patients with chronic fatigue syndrome, randomized to treatment with Ampligen or a placebo. The study's primary endpoint was improvement in treadmill exercise tolerance at week 40. Hemispherx announced positive results from the Ampligen study in May 2004, claiming that Ampligen patients demonstrated a 17.4% improvement in treadmill exercise tolerance compared to a 4.3% improvement for placebo patients -- a net difference of 13.1%. The result was statistically significant with a p value of 0.047. However, in May 2006, results from this same study were presented at a medical meeting showing a 12.9% difference in treadmill exercise performance between Ampligen and placebo that was not statistically significant.
Depending on which data presentation you believe, the Ampligen study was either a success or a failure. By rejecting Ampligen in 2009, FDA clearly sided with the latter view. In March, Hemispherx published the full data from the Ampligen trial in the open-access science journal PLOS One. Once again, the study results changed and got worse. Ampligen-treated patients with chronic fatigue syndrome entered the study with a mean, baseline treadmill exercise duration of 576 seconds. After 40 weeks of treatment, mean exercise duration rose to 672 seconds, or a 16.7% improvement. The placebo patients began the study with a mean, baseline treadmill exercise duration of 588 seconds and ended at 616 seconds, or an improvement of 4.8%. That works out to a placebo-adjusted improvement in exercise duration for Ampligen of 11.9%. This benefit doesn't appear to be statistically significant, however. The study, as published in PLOS One, makes no mention of this intra-group comparison reaching statistical significance. The Ampligen study appears to have failed -- which gibes with the FDA's decision to reject the drug and call for a new study to be conducted. Hemispherx has not invested the money and time necessary to run a new Ampligen study, choosing instead to change the way the primary endpoint of treadmill exercise duration was measured. Instead of comparing the two groups of Ampligen and placebo patients, Hemispherx switched to analyzing the exercise data using each individual patient as their own comparator. On this "intra-patient" basis, Ampligen improved exercise duration by 36.5% compared to a 15.2% improvement for placebo patients. The net difference of 21.3% was "statistically significant" with a p value of 0.047, according to the PLOS One study. Hemispherx CEO William Carter and Medical Director David Strayer were lead authors of the study. William Mitchell, a Hemispherx director, is also listed as a study author. Hemispherx also conducted other, post-hoc analyses claiming to show that patients who were able to exercise longer following Ampligen therapy had improved quality of life and reduced dependency on concomitant medications compared to Ampligen patients who couldn't exercise longer. All of these new analyses of the Ampligen data were done retrospectively, or long after the study was completed. Hemispherx has made no effort to confirm any of these findings with new clinical trials.
Following a meeting with FDA officials in June, Hemispherx claims the agency agreed to review the new analyses of the Ampligen study in lieu of data from a new clinical trial. However, Hemispherx also warned that, "Whether these data provide adequate evidence of efficacy will ultimately be a review issue, and there can be no assurance the FDA will conclude the data are adequate to support approval of the Ampligen NDA." Investors would be wise to take that warning seriously. A postscript: Omitted from this column is a retelling or discussion of Hemispherx management's questionable actions and misleading statements made during the previous Ampligen review cycle in 2009. I covered Hemispherx extensively during this period, so feel free to go back and read my prior stories: Hemispherx's CFS Drug Is a Long Shot Hemispherx Builds False Hope on Old Data Hemispherx, in FDA Limbo, Seeks More Cash Hemispherx Hasn't Called FDA on Ampligen Review Hemispherx Cops to Ampligen Delay Hemispherx's Ampligen Dealt Fatal FDA Blow --Written by Adam Feuerstein in Boston. >To contact the writer of this article, click here: Adam Feuerstein. >To follow the writer on Twitter, go to http://twitter.com/adamfeuerstein. >To submit a news tip, send an email to: firstname.lastname@example.org. Follow TheStreet on Twitter and become a fan on Facebook.